Human Models of Selective Insulin Resistance: Pancreatic Clamp

ConditionsInsulin Resistance Hyperinsulinemia Metabolic Dysfunction Associated Steatotic Liver Disease Non-Alcoholic Fatty Liver Disease Prediabetic State Obesity

Trial statusNot yet recruiting

Trial phasePhase 1

Trial typeInterventional

Biological sexAll

Age18-65

SponsorColumbia University

About this trial

This is a single-center, prospective, randomized, controlled (crossover) clinical study designed to investigate the impact of lowering insulin levels on hepatic glucose production (HGP) vs de novo lipogenesis (DNL) in people with insulin resistance. The investigators will recruit participants with a history of overweight/obesity and evidence of insulin resistance (i.e., fasting hyperinsulinemia plus prediabetes and/or impaired fasting glucose and/or Homeostasis Model Assessment of Insulin Resistance \[HOMA-IR\] score \>=2.73), and with evidence of metabolic dysfunction-associated steatotic liver disease (MASLD). Participants will undergo two pancreatic clamp procedures -- one in which serum insulin levels are maintained near hyperinsulinemic baseline (Maintenance Hyperinsulinemia or "MH" Protocol) and the other in which serum insulin levels are lowered by 50% (Reduction toward Euinsulinemia or "RE" Protocol). In both clamps the investigators will use stable-isotope tracers to monitor hepatic glucose and triglyceride metabolism. The primary outcome will be the impact of steady-state clamp insulinemia on HGP vs DNL.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Men and women, ages 18-65 years

Body mass index of 27-50 kg/m2

Able to understand written and spoken English and/or Spanish

Prediabetes: Hemoglobin A1c 5.7-6.4%

Disqualifiers

Unable to provide informed consent in English or Spanish

Unwillingness to use only bedpan or urinal to void or to refrain from non-emergent mobile device use during the clamp

Documented weight loss of ≥ 5% of baseline within the previous 3 months

Abnormal blood pressure (including on treatment, if prescribed)

Trial design

Design model

Crossover

Treatments tested in this trial

Insulin human
Drug
Insulin infusion rate (IIR) will be determined either to maintain fasting serum insulin levels (MH protocol) or to reduce fasting serum insulin levels by approximately 50% toward euinsulinemia (RE protocol).
Octreotide Acetate
Drug
Octreotide will be infused at 30 ng/kg/min to suppress endogenous insulin, glucagon, and growth hormone secretion. Co-administered with glucagon and rhGH.
Glucagon
Drug
Glucagon will be replaced at a constant rate of up to 0.65 ng/kg/min to maintain baseline counterregulatory response. Co-administered with octreotide and rhGH.
Growth Hormone, Human
Drug
Recombinant human growth hormone (rhGH) will be replaced at a constant rate of up to 3 ng/kg/min to maintain baseline counterregulatory response. Co-administered with octreotide and glucagon.
20% D-glucose (aq)
Drug
20% D-glucose (aq) (D20W) will be administered to counteract hypoglycemia or strongly downward blood glucose trends, as needed.
[6,6-2H2] D-glucose
Diagnostic test
Stable isotope tracer administered to calculate glucose kinetics during pancreatic clamp.
[1-13C1] sodium acetate
Diagnostic test
Stable isotope tracer administered to calculate de novo lipogenesis during pancreatic clamp.
Nestle BOOST Plus
Dietary supplement
Nutritional supplement will be administered to provide standardized "mixed meals" prior to the pancreatic clamp.
KIND Bar
Dietary supplement
Energy bar snack will be administered the evening before the pancreatic clamp.
Harvard Apparatus PHD ULTRA CP syringe pump
Device
Syringe pump used for highly precise administration of insulin, octreotide/glucagon/rhGH, and D20W (as needed) even at low infusion rates.
Yellow Springs Instruments (YSI) 2500 Biochemistry Glucose/Lactate Analyzer
Device
Glucose oxidase analyzer used to detect plasma glucose levels at the point of care. YSI have been the gold standard in clamp studies for many years. Two machines will run in parallel to ensure accuracy of results.

Treatment groups

36 Participants

are divided into 2 treatment groups

Group A: Maintenance hyperinsulinemia (MH) Protocol then Reduction toward Euinsulinemia (RE) ProtocolExperimental treatment 11 interventions

Group B: Reduction toward euinsulinemia (RE) protocolExperimental treatment 11 interventions

Trial outcomes

Primary outcomes

Hepatic de novo lipogenesis (DNL) (absolute value)

Percent incorporation of newly synthesized fatty acids into plasma or very low-density lipoprotein (VLDL) triglyceride (TG) during pancreatic clamp procedures. (Unit: %)

Time frame